Transplantation of retrovirally resistant cells has been proposed as a therapeutic modality to treat HIV infected patients. We developed an animal model in which to explore the safety of administration of retrovirally resistant cells into susceptible animals. Using a murine model of acquired immunodeficiency induced by retroviruses, we established that there is a critical balance between susceptible and resistant lymphoid cells that determines whether the animals succumb to disease, or achieve long term resistance in that only animals containing >50% resistant cells were completely protected from disease. Critically, no changes in tropism of the infective retrovirus were detected during the course of the study . To assess the anti-retroviral mechanisms that confer resistance in this model, we have constructed animals in which the resistant cell population is deficient in receptors for IFN-gamma and are pursuing construction of resistant strain mice deficient in perforin, required for some aspects of cell mediated cytotoxicity. The latter mice have been infected and results pending. This program directly supports the mission of the Center by creating an animal model to allow us to anticipate the safety and potential efficacy of therapeutic modalities involving tranplantation of lymphoid populations resistant to HIV into HIV infected humans. One such protocol involving transplant of baboon bone marrow is already in progress.